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Second Study Shows Treatment May Increase Drug Resistance

July 9, 2004

A single dose of the drug nevirapine given at the beginning of labor, when combined with a short course of the anti-HIV drug AZT (zidovudine), dramatically reduces a woman's chances of passing HIV on to her child, according to a study of Thai women funded in part by the National Institute of Child Health and Human Development of the National Institutes of Health.

The study authors, publishing in the July 15 New England Journal of Medicine, found that the two drug combination reduces transmission of the virus to below 2 percent, similar to what is achieved with more expensive three-drug regimens routinely prescribed in developed countries.

However, in a second NIH-funded study in the same issue of the journal, the same researchers followed the progress of women from the first study who developed low levels of CD4+ cells after they had given birth. CD4+ cells are a type of immune cell and low CD4+ levels indicate that the HIV infection is growing worse and advancing toward AIDS. The researchers found that some women who, after they had given birth, developed low CD4 levels and who had received single-dose nevirapine, harbored a strain of the virus that had grown resistant to nevirapine. Women with resistant virus were less likely to show a decrease in HIV levels when receiving anti-HIV therapy that contained the drug nevirapine than women without such resistance. This second study also received funding from NICHD, as well as from NIH's National Institute of Allergy and Infectious Diseases.

In Thailand at the time of the study, the standard treatment to reduce the risk of pregnant women passing HIV on to their infants was a regimen of AZT, given during labor and delivery, and to newborns for 1 week. The standard treatment also called for infants to formula feed, rather than breastfeed, to reduce the risk of transmitting the virus through breast milk.

The lead author of the first study was Marc Lallemant, M.D., Institut de Recherche pour le Développement, in Paris, France. In 2001, Dr. Lallemant and his coworkers began a study to determine whether adding nevirapine to the standard therapy would further reduce transmission of HIV from mother to child. Specifically, the researchers sought to determine if adding a single dose of nevirapine to the mothers during labor and to their infants after birth to the standard AZT regimen would reduce transmission of the virus. Enrollment in the trial was offered to 1844 pregnant Thai women infected with HIV who were receiving care at 37 hospitals throughout Thailand.

All women in the study received AZT starting at the beginning of the last trimester, and infants were given the standard AZT treatment. The women were then assigned at random to one of three groups. In the first group, the women received a single dose of nevirapine at the beginning of labor and their infants were given a single dose of nevirapine at 48 to 72 hours of age. In the second group, the women received nevirapine and their infants received a placebo instead of nevirapine, while in the third group, both the women and their infants received placebos instead of nevirapine.

In May of 2002, the AZT-alone arm of the study was discontinued after the study's Data and Safety Monitoring Board conducted an interim analysis and found that women receiving nevirapine were much less likely to pass HIV on to their infants. Data and Safety Monitoring Boards are independent panels that periodically monitor the study's data to see whether any treatments need to be changed.

The researchers resumed the study, however, to determine if giving a dose of nevirapine to the infants-in addition to giving one dose of the mothers-would further reduce transmission of the virus.

Among the women who gave birth before the interim analysis, HIV was transmitted from mother to child at a rate of 1.1 percent in the group in which both mothers and infants received nevirapine. The transmission rate was 6.3 percent for the group in which both mothers and infants received AZT only. After the study's completion, the final analysis also showed the rate of mother-to-infant HIV transmission was 2.0 percent in the group in which both mother and infant received nevirapine, compared to 2.8 percent for the group in which only the mother received nevirapine. Overall, these two rates were not statistically different. However, in women with low CD4+ levels or higher HIV levels, giving nevirapine to both mothers and infants seemed to reduce transmission of the virus slightly more than did giving nevirapine to mothers alone.

By comparison, in the U.S., where pregnant women with HIV infection usually receive three anti-HIV drugs starting in the second trimester, the mother-to-child transmission rate is under 2 percent, said the NICHD project officer for the study, Lynne Mofenson, M.D., Chief of the Pediatric, Adolescent and Maternal AIDS Branch.

"The study shows that a short, inexpensive two-drug regimen can be applied in developing countries and achieve success rates near those seen with the current, more complex and expensive treatments used in the U.S.," Dr. Mofenson said.

However, previous studies have shown that a few weeks after delivery, some women who receive a single dose of nevirapine may harbor HIV that is resistant to nevirapine, Dr. Mofenson said. She explained that after treatment with nevirapine, low levels of the drug may remain in the blood for up to 3 weeks. Under these conditions, HIV strains that are susceptible to nevirapine quickly die off, while the few viruses from a strain that is naturally resistant to the drug multiply.

When nevirapine is no longer present in the blood, the HIV strains that are resistant to the drug fade and strains that are sensitive to the drug return, Dr. Mofenson added. However, the resistant strains may be present at low levels, and researchers do not know if the presence of this resistant strain might alter the effectiveness of nevirapine in women who later become sick and require treatment.

In a second study, Gonzague Jourdain, MD, of the Harvard School of Public Health, and his colleagues, followed the progress of 269 women from the first study. These women later required anti-HIV therapy because they developed low CD4+ counts at some time-often many months-after they had given birth. In Thailand, the standard treatment for HIV-infected persons with low CD4+ cell counts is a regimen of three anti-HIV drugs, which includes nevirapine. The researchers compared the women's responses after 6 months of three anti-HIV drug therapy, which included nevirapine. Of the 269 women, 221 had received a single dose of nevirapine and 48 had not.

Compared to women who had not received nevirapine during labor, those who had received the drug during labor were less likely to achieve maximum HIV suppression. Maximal viral suppression is a measure the researchers took to determine if the treatment had succeeded in reducing the levels of HIV in the blood. Specifically, the researchers considered maximal viral suppression to be less than 50 copies of HIV per 1 milliliter of plasma.

After 6 months of therapy, the researchers were able to determine the plasma levels of HIV for 229 women. Of these, 49 percent of 188 women who had received a single dose of nevirapine during labor experienced maximal viral suppression. In comparison, 68 percent of 41 women who had not received nevirapine experienced maximal viral suppression. High levels of HIV in the blood before therapy was begun were also associated with decreased likelihood of maximal viral suppression, regardless of whether or not the women had received a single dose of nevirapine during labor.

However, the women did not differ in some other indicators of response to therapy. After 6 months of treatment, the women showed no difference in the amount of increase in CD4+ levels or in the amount of weight they had regained. Regaining lost weight is an indication that HIV patients are responding to drugs that suppress the virus.

The researchers also looked for HIV strains that were resistant to nevirapine in stored blood samples taken 10 days after the women had given birth. In those women for whom blood samples were available, 32 percent of 209 women who had received a single dose of nevirapine during labor had nevirapine-resistant HIV. By comparison, none of the 47 women who had not received a single dose of nevirapine during labor had nevirapine resistant HIV. Women who developed resistance were more likely to have had lower CD4+ levels and higher HIV levels before the second study began than women who did not develop resistance.

In the women who had received a single dose of nevirapine during labor, those who had viral strains resistant to nevirapine 10 days after they gave birth were least likely to experience maximal viral suppression after 6 months of treatment-38 percent of 61 women. In comparison, 52 percent of 119 women who had received a single dose of nevirapine but did not have a resistant strain of the virus achieved maximal viral suppression.

Dr. Mofenson noted that women with higher CD4+ levels and lower levels of HIV are at less risk for developing nevirapine resistance than those with low CD4+ counts and higher viral levels.

Given these facts, the study authors wrote that single dose nevirapine therapy combined with the standard AZT treatment would be an important tool for preventing the spread of HIV in developing countries and were optimistic that methods could be found for preventing or treating nevirapine resistance.

Dr. Mofenson noted that the researchers and the Thai Ministry of Public Health have studies under way to find ways to reduce the risk of nevirapine resistance and to determine the most effective therapy for women who have received a single dose of nevirapine. The Thai government now considers the combination of short course AZT with single dose nevirapine as the standard for preventing mother to child transmission of HIV.

In addition to support from NIH, this research was also supported by the Agence Nationale de Recherches sur le Sida; the Ministry of Public Health, Thailand; the Institut de Recherche pour le Développement, France; the Institut National d'Etudes Démographiques, France; and the Department of Technical and Economic Cooperation, Thailand.

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The NICHD is part of the National Institutes of Health (NIH), the biomedical research arm of the federal government. NIH is an agency of the U.S. Department of Health and Human Services. The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. NICHD publications, as well as information about the Institute, are available from the NICHD Web site, http://www.nichd.nih.gov, or from the NICHD Information Resource Center, 1-800-370-2943; e-mail NICHDInformationResourceCenter@mail.nih.gov.